miR-146a-5p acts as a negative regulator of TGF-β signaling in skeletal muscle after acute contusion

Yaying Sun, Yan Li, Hui Wang, Hongyun Li, Shaohua Liu, Jiwu Chen, and Hao Ying

Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai 200040

Acta Biochim Biophys Sin 2017, 49: 628–634; doi: 10.1093/abbs/gmx052

Growing evidence suggests the importance of microRNAs (miRNAs) in stress signaling pathways. Transforming growth factor-β (TGF-β) is a potent cytokine that promotes the development of skeletal muscle fibrosis after acute contusion. However, how miRNAs are involved in TGF-β signaling and confer the robustness of TGF-β-induced fibrotic response remains to be fully elucidated. Here, we demonstrated that miR-146a-5p (miR-146) levels were reduced in a fibrotic mouse model after acute muscle contusion. It was also found that TGF-β treatment decreased the expression of miR-146 in vitro in a dose- and time-dependent manner. In addition, overexpression of Smad3 and Samd4, two key players in TGF-β signaling, suppressed the expression of miR-146 in muscle cells. Overexpression of miR-146 inhibited the expressions of fibrosis markers both in vitro and in vivo. Moreover, increase in the expression of miR-146 in muscle cells was able to attenuate the effect of TGF-β on the expressions of fibrosis markers. Mechanistic analysis revealed that Smad4 is a direct target of miR-146 in muscle cells. Furthermore, the anti-fibrotic effect of miR-146 could be blocked by overexpression of Smad4 in vivo. These results suggest that Smad4 is down-regulated by miR-146 in skeletal muscle. Taken together, our results indicate that the anti-fibrotic miR-146 is a component of TGF-β signaling. It is down-regulated by Smad protein, and can inhibit the expression of Smad4. Our study suggests that miR-146 might have a therapeutic potential to reduce skeletal muscle fibrosis after injury.

miR-146 expression is decreased during fibrosis

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